Download Bridging Chemistry and Biology for New Classes of Imaging Probes

Bridging Chemistry and Biology for New Classes of Imaging Probes
and Therapeutic Drugs
Jin Wang
Assistant Professor and CPRIT Scholar
Department of Pharmacology
Baylor College of Medicine
Houston, TX 77030
[email protected]
Abstract
The overarching goal for my research is to develop new tools for advancing biological
research and new therapies for improving human health at the interface of chemistry and
biology. My group has made major contributions in the areas of ratiometric redox probes and
small molecule drugs. Glutathione (GSH) is the most abundant non-protein thiol in eukaryotic
cells. Together with its oxidized partner (GSSG), GSH maintains cellular redox homeostasis,
regulates protein functions through S-glutathionylation, and acts as a signaling molecule to
directly activate gene expression. Currently, the concentration of intracellular GSH is derived
from either cell lysates or GSH-S-transferase (GST) dependent probes. These approaches,
however, cannot provide information about the real-time dynamics of GSH concentration
changes. We developed a fluorescent probe that can reversibly react with GSH and
quantitatively monitor the real-time GSH dynamics in living cells for the first time. This new GSH
probe enables unprecedented opportunities to study GSH spatiotemporal dynamics, which will
revolutionize our understanding of its physiological and pathological roles in living cells. On the
other hand, we also developed a small molecule inhibitor of steroid receptor coactivator-3 (SRC3) as a novel targeted cancer therapy. The Holy Grail of drug discovery is to render small
molecules the power of biologics to regulate protein-protein interactions. SRC-3 is a large, nonstructured nuclear protein which regulates many signaling pathways that are essential for tumor
formation. Through high throughput screening and medicinal chemistry optimization, we
identified SI-2 that can direct interact with SRC-3 and selectively reduce its transcriptional
activities and protein concentrations, leading to selective induction of breast cancer cell death
with a low nM IC50 value, and inhibition of primary tumor growth in a breast cancer mouse model.
This work will not only potentially improve breast cancer treatment through the development of a
‘first-in-class’ drug that targets oncogenic coactivators, but also encourage other researchers to
develop strategies to target protein-protein interactions that are designated as ‘important but
undruggable’ targets in the future.